DNA repair mechanisms that promote insertion-deletion events during immunoglobulin gene diversification

生物 遗传学 免疫球蛋白基因 多元化(营销策略) 基因缺失 DNA 基因 DNA修复 抗体 业务 突变体 营销
作者
Qian Hao,Chuanzong Zhan,Chaoyang Lian,Simin Luo,Wenyi Cao,Binbin Wang,Xia Xie,Xiaofei Ye,Tuantuan Gui,Claudia Voena,Chiara Pighi,Xiaogang Wang,Jian-Jun Guo,Xin Wang,Pengfei Dai,Yanni Cai,Xiaojing Liu,Shengqun Ouyang,Shiqi Sun,Qianwen Hu,Jun Liu,Youqiong Ye,Jingkun Zhao,Aiguo Lu,Ji‐Yang Wang,Chuanxin Huang,Bing Su,Fei‐Long Meng,Roberto Chiarle,Qiang Pan‐Hammarström,Leng-Siew Yeap
出处
期刊:Science immunology [American Association for the Advancement of Science (AAAS)]
卷期号:8 (81) 被引量:7
标识
DOI:10.1126/sciimmunol.ade1167
摘要

Insertions and deletions (indels) are low-frequency deleterious genomic DNA alterations. Despite their rarity, indels are common, and insertions leading to long complementarity-determining region 3 (CDR3) are vital for antigen-binding functions in broadly neutralizing and polyreactive antibodies targeting viruses. Because of challenges in detecting indels, the mechanism that generates indels during immunoglobulin diversification processes remains poorly understood. We carried out ultra-deep profiling of indels and systematically dissected the underlying mechanisms using passenger-immunoglobulin mouse models. We found that activation-induced cytidine deaminase-dependent ±1-base pair (bp) indels are the most prevalent indel events, biasing deleterious outcomes, whereas longer in-frame indels, especially insertions that can extend the CDR3 length, are rare outcomes. The ±1-bp indels are channeled by base excision repair, but longer indels require additional DNA-processing factors. Ectopic expression of a DNA exonuclease or perturbation of the balance of DNA polymerases can increase the frequency of longer indels, thus paving the way for models that can generate antibodies with long CDR3. Our study reveals the mechanisms that generate beneficial and deleterious indels during the process of antibody somatic hypermutation and has implications in understanding the detrimental genomic alterations in various conditions, including tumorigenesis.
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